Advances in development of bevacizumab, a humanized anti-angiogenic therapeutic monoclonal antibody targeting VEGF in cancer cells

Vascular endothelial growth factor A (VEGF) is a potent proangiogenic growth factor that stimulates the proliferation, migration, and survival of endothelial cells. As one of the more important proteins also expressed by tumor cells, VEGF is recognized as an essential regulator of normal and abnormal blood vessel growth. In 1993, it was shown that a monoclonal antibody that targeted VEGF results in a dramatic suppression of tumor growth in vivo, which led to the development of bevacizumab (Avastin; Genentech), a humanized therapeutic form of this anti-VEGF antibody blocking angiogenesis is an effective approach to treat human cancer. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high affinity VEGF receptors. VEGF is a sub-family of growth factors, to be specific, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.